Tracking pericyte dysfunction in Alzheimer's disease: The emerging role of cerebrospinal fluid platelet-derived growth factor receptor-β.

Abstract

Growing human and experimental evidence redefine Alzheimer's disease (AD) as a neurovascular disorder because the early neurovascular unit (NVU) injury triggers proteinopathy. Among NVU, pericytes are a pivotal regulator of capillary tone, blood-brain barrier (BBB) integrity, and amyloid-β (Aβ) clearance. Injured or lost pericytes promote non-selective transcytosis, induce endothelial de-zonation, weaken tight junctions, and drive heterogeneous capillary flow and rarefaction. Here, we collect data from clinical imaging, cerebrospinal fluid (CSF) biomarkers, and transgenic mice with platelet-derived growth factor receptor-β (PDGFRβ) signal defects to discuss the role of CSF soluble PDGFRβ (sPDGFRβ) as a marker of BBB damage across the AD continuum. During normal aging, sPDGFRβ rises slightly, consistent with low-grade pericyte stress. In mild cognitive impairment, sPDGFRβ is elevated and associates with BBB breakdown and accelerated cognitive decline, often independent of core AD biomarkers, suggesting early vascular changes before AD onset. In early AD, pericyte dysfunction (characterized by elevated sPDGFRβ) attenuates pericyte-dependent Aβ processing and endothelial lipoprotein receptor-related protein 1-mediated Aβ efflux, leading to impaired perivascular drainage and favoring Aβ40-rich vascular deposition and capillary cerebral amyloid angiopathy. During AD progression, despite persistent leakage, sPDGFRβ frequently plateaus, reflecting severe pericyte depletion and reduced discrimination of disease stage. We propose a practical approach that integrates sPDGFRβ with BBB imaging analysis and Aβ biomarkers to distinguish between parenchymal-dominant and vascular-dominant pathology in AD. These indicators can identify patients at high risk of developing amyloid-related imaging abnormalities during anti-amyloid therapy and can serve as pharmacodynamic endpoints for BBB-stabilizing or pericyte-targeted interventions to advance personalized dementia care.